Chemotherapy - Pharmacology for Medical Graduates, 4th Updated Edition

Conjugation is the transfer of genetic material carrying resistance between bacteria by direct contact through sex pilus, e.g. Escherichia coli resistance to streptomycin.

There are several mechanisms by which an organism can develop resistance to an AMA. The important mechanisms are as follows:

• 1.

  Production of inactivating enzymes : For example, staphylococci, gonococci and E. coli produce β-lactamases that can destroy some of the penicillins and cephalosporins.

• 2.

  An efflux pump mechanism : It is a mechanism that prevents the accumulation of the drug in the microorganism, e.g. resistance of gram-positive and gram-negative bacteria to tetracyclines, chloramphenicol, macrolides, etc.

• 3.

  Decreased entry of AMA into the organism due to alteration in the channel/transporter required for its entry into the organism.

• 4.

  Alteration of the binding site : For example, change in penicillin-binding proteins (PBPs) in case of certain pneumococci with decreased affinity for penicillins.

• 5.

  Absence of metabolic pathway : For example, sulphonamide-resistant bacteria can utilize preformed folic acid without the need for usual metabolic steps.

It is done by:

• 1.

  Selecting right AMA.

• 2.

  Giving right dose of the AMA for proper duration.

• 3.

  Proper combination of AMAs, e.g. in tuberculosis (TB), multidrug therapy (MDT) is used to prevent development of resistance to antitubercular drugs by mycobacteria.

Superinfection is associated with suppression/change of normal flora in the body following treatment with certain antimicrobials. The pathogenesis of superinfection is described in Fig. 11.2 .

Pathogenesis of superinfection. (A) Absence of bacteriocins promotes growth of pathogens. (B) Alteration in normal flora favours utilization of nutrients by pathogens.

The sites involved in superinfection are those body cavities that have direct communication with the exterior, i.e. rectum, oral cavity, vagina, lower urinary tract, upper respiratory tract, etc. ( Table 11.1 ).

Superinfection is common in immunocompromised conditions, such as diabetes, malignancy and AIDS, and also during prolonged corticosteroid therapy. It can be minimized by (i) using specific AMAs, (ii) avoiding unnecessary use of AMAs and (iii) use of probiotics, e.g. Lactobacillus .

The effectiveness of chemoprophylaxis depends on the selection of a specific AMA, its dosage, time of initiation and duration of antimicrobial therapy. The suggested chemoprophylactic regimens are listed in Table 11.2 .

• Empirical therapy: It is the use of AMAs before identification of causative organism or availability of susceptibility test results, e.g. combination of cefotaxime, vancomycin and ampicillin is used as empirical therapy for suspected bacterial meningitis (before test results are available) to cover possible organisms likely to cause meningitis.

• Definitive therapy: It involves the use of AMA after identification/susceptibility tests of the causative organism responsible for the disease.

• 1.

  To broaden the spectrum of activity in mixed bacterial infections : Intra-abdominal, pulmonary, hepatic, pelvic, brain abscesses, etc., are often due to both aerobic and anaerobic organisms. Hence, they require antimicrobial combination therapy.

  • ■

    Metronidazole + ceftriaxone for brain abscess

• 2.

  To broaden the spectrum of action in severe infections when the aetiology is not known : Combination of cefotaxime, vancomycin and ampicillin is used for empirical therapy of suspected bacterial meningitis. Later, the AMA should be selected according to the type of organism, culture and sensitivity results.

• 3.

  To increase antibacterial activity in the treatment of specific infections (for synergistic effect)

  • ■

    Ampicillin (bactericidal) + gentamicin (bactericidal) for enterococcal endocarditis

  • ■

    Carbenicillin + gentamicin for infections due to Pseudomonas

    • Penicillins, by inhibiting bacterial cell wall synthesis, facilitate the entry of gentamicin into the bacterial cell (synergistic effect) resulting in more complete eradication of the organism.

  • ■

    Sulphamethoxazole + trimethoprim for Pneumocystis jiroveci pneumonia (see p. 377 for mechanism of action)

  • ■

    Rifampin (cidal) + dapsone (static) in leprosy – synergistic effect

• 4.

  To prevent emergence of resistant microorganisms : In TB, leprosy and HIV infection, combination therapy is used.

• 5.

  To reduce duration of therapy : MDT is used in TB and leprosy.

• 6.

  To reduce adverse effects : AMB and flucytosine in cryptococcal meningitis: The dose-dependent toxicity (especially nephrotoxicity) of AMB is decreased due to reduction in dosage (see p. 425).

• 1.

  Increased toxicity , e.g. vancomycin with tobramycin may cause enhanced nephrotoxicity.

• 2.

  Increased cost .

• 3.

  Decreased antibacterial activity due to improper combinations, e.g. in pneumococcal meningitis, activity of penicillin G (bactericidal) against pneumococci will decrease if combined with tetracycline (bacteriostatic). Penicillins act mainly on rapidly multiplying bacteria; tetracycline inhibits multiplication of bacteria because of its static effect, thus reducing effect of penicillins.

• 4.

  Increased likelihood of superinfection .

• 5.

  Irrational combination of AMAs can lead to development of resistance .

• 1.

  Age: Use of chloramphenicol in premature infants may produce grey baby syndrome because metabolic functions of liver and renal excretion are not fully developed. Sulphonamides in neonates can cause kernicterus.

  • Renal function declines with age; hence, elderly patients are more prone to ototoxicity and nephrotoxicity with aminoglycosides due to their reduced clearance by kidney.

• 2.

  History of allergy: In patients with history of asthma, allergic rhinitis, hay fever, etc., there is an increased risk of penicillin allergy; hence, such drugs should be avoided in them.

• 3.

  Genetic abnormalities: Primaquine, pyrimethamine, sulphonamides, sulphones, FQs, etc., may cause haemolysis in patients with G6PD deficiency.

• 4.

  Pregnancy: Most of the AMAs cross placental barrier and may affect the developing fetus. The risk of teratogenicity is highest during the first trimester. For example, use of tetracyclines during pregnancy may affect fetal dentition and bone growth. There is an increased incidence of hepatotoxicity with tetracycline in pregnant women.

• 5.

  Host defences: In immunocompromised patients (AIDS, leukaemias and other malignancies), normal defence mechanisms are impaired – bacteriostatic drugs may not be adequate; hence bactericidal agents should be used to treat infection.

• 6.

  Hepatic dysfunction: In patients with hepatic dysfunction, drugs like chloramphenicol, erythromycin and rifampin should be avoided or require dose reduction to minimize toxic effects.

• 7.

  Renal dysfunction: In renal failure, drugs that are eliminated via kidney can accumulate in the body and cause severe toxic effects. Hence, aminoglycosides, vancomycin, AMB, FQs, etc., should be avoided or require dose reduction in patients with impaired renal function.

• 8.

  Local factors

  • (a)

    Antimicrobial activity of sulphonamides is markedly reduced in the presence of pus.

  • (b)

    The activity of aminoglycosides is enhanced at alkaline pH.

Factors affecting selection of an antimicrobial agent.

• 1.

  Route of administration: Depending on the severity and site of infection, AMAs have to be chosen. Some of the AMAs can be administered orally as well as parenterally. For mild-to-moderate infections, oral route is usually preferred, but for severe infections like endocarditis and meningitis, parenteral AMAs are preferred during initial stages of therapy. Some AMAs like aminoglycosides are not effective orally; they are administered parenterally for systemic infections.

• 2.

  The spectrum of antimicrobial activity: It is an important factor while selecting an AMA especially during empirical therapy.

• 3.

  Bactericidal/bacteriostatic effect: Bactericidal drugs kill organisms, while static drugs inhibit growth and multiplication. In immunocompromised states, the host-defence mechanisms are impaired; hence, bactericidal drugs are required even for trivial infections.

• 4.

  Cost of AMA: The cost of treatment has to be considered while selecting an AMA. The expensive antimicrobials should not be used routinely when alternative cheaper and effective AMAs are available.

• 5.

  Pharmacokinetic/pharmacodynamic considerations

  • ■

    Time-dependent inhibition: This is observed with certain AMAs like β-lactams and glycopeptides. Their antimicrobial action depends on the duration of time the drug concentration remains above the MIC in the dosing interval. Thus, they are administered in multiple doses.

  • ■

    Concentration-dependent killing: For aminoglycosides and FQs, the antimicrobial effect depends on the ratio of peak plasma concentration to MIC. A single daily dose of aminoglycosides is as/more effective than multiple doses.

  • ■

    Ability to penetrate into the infected area

    • ■

      Ability to cross the blood–brain barrier (BBB): Clindamycin is effective against anaerobes, but not useful for anaerobic brain abscess as it does not reach cerebrospinal fluid (CSF) and brain. Anaerobic brain abscess can be treated effectively with third-generation cephalosporins or combination of metronidazole and chloramphenicol.

    • ■

      Levofloxacin attains good concentration in the lung, skin/soft tissues and urinary tract – produces high cure rates in community-acquired pneumonia, skin infections, etc.

In severe infections, empirical therapy with antimicrobial drug combination should be initiated depending on the clinical diagnosis. Later, the AMA should be selected according to the type of organism, culture and sensitivity reports. The bacterial resistance to AMAs and cross-resistance should also be considered while selecting an AMA.

para -Aminobenzoic acid (PABA) is a precursor of folic acid which is essential for growth and multiplication of many bacteria. Sulphonamides, being structurally similar to PABA, competitively inhibit folate synthase enzyme and prevent the formation of folic acid, thereby producing bacteriostatic effect. They are not effective in the presence of pus as it is rich in PABA, purines and thymidine. Mammalian cells do not synthesize folic acid, but utilize folic acid present in diet, hence are unaffected by sulphonamides.

Most of the bacteria have developed resistance to sulphonamides. It could be due to:

• 1.

  Decreased affinity of folate synthetase for the drug

• 2.

  Efflux of the drug by bacteria

• 3.

  Development of alternate metabolic pathway for folate synthesis

All systemic-acting sulphonamides are well absorbed from the gut. They are bound to plasma proteins, particularly albumin. Sulphonamides are distributed in almost all tissues of the body including CSF. They cross placental barrier and reach fetal circulation; they are metabolized in liver mainly by acetylation. The acetylated products have no antibacterial activity but retain the toxic potential of the parent compound. Sulphonamides are excreted partly unchanged and partly as metabolic products.

• 1.

  The acetylated products of sulphonamides are poorly soluble in acidic urine and may cause crystalluria, haematuria or even obstruction to urinary tract. This may be avoided by taking plenty of water and alkalinizing the urine.

• 2.

  Hypersensitivity reactions include skin rashes, itching, drug fever and exfoliative dermatitis. Stevens–Johnson syndrome is the most severe type of hypersensitivity reaction characterized by fever, erythema multiforme and ulceration of mucous membranes.

• 3.

  In patients with glucose-6-phosphate dehydrogenase deficiency, sulphonamides may cause acute haemolytic anaemia.

• 4.

  Rarely cause hepatitis and suppression of bone marrow.

• 5.

  Use of sulphonamides in neonates, especially in premature babies, may cause displacement of bilirubin from plasma proteins. The free bilirubin can cross BBB and get deposited in the basal ganglia resulting in kernicterus.

Sulphonamides potentiate the effect of phenytoin, methotrexate (MTX), oral anticoagulants and oral hypoglycaemic agents (sulfonylureas) by inhibiting their metabolism and displacing them from plasma protein binding sites.

Sulphonamides alone are rarely used now for systemic infections. They are used in combination with other AMAs.

• 1.

  Sulphadoxine and pyrimethamine are used in combination with artesunate in the treatment of chloroquine-resistant Plasmodium falciparum malaria.

• 2.

  Sulphadiazine and pyrimethamine combination is the drug of choice for toxoplasmosis.

• 3.

  Nocardiosis: Sulphamethoxazole in combination with trimethoprim is used.

• 4.

  Sulphamethoxazole in combination with trimethoprim is used in the treatment of P. jiroveci infection in patients with AIDS.

• 5.

  Sodium salt of sulphacetamide is used exclusively for the treatment of ophthalmic infections. It is administered as eye drops or eye ointment. It is preferred because of:

  • (a)

    High aqueous solubility

  • (b)

    Neutral pH and nonirritant nature of the drug

  • (c)

    Good penetrability on topical administration

  • (d)

    Low incidence of hypersensitivity reactions

  • (e)

    Low cost

• 6.

  Silver sulfadiazine and mafenide are used topically for preventing infection of burn wound. Silver sulfadiazine slowly releases silver ions which are toxic to microorganisms. It is not effective in the presence of pus and tissue fluid.

• 7.

  Sulphasalazine is useful in the treatment of inflammatory bowel disease and rheumatoid arthritis.

• 8.

  Rheumatic fever: Sulphadiazine can be used for prophylaxis of rheumatic fever.

Cotrimoxazole (sulphamethoxazole and trimethoprim in a dose ratio of 5:1) produces sequential blockade , i.e. two drugs interfere with two successive steps in the same metabolic pathway; hence, their combination produces supra-additive effect. Sulphamethoxazole inhibits folate synthetase, whereas trimethoprim inhibits folate reductase enzyme. The pharmacokinetic properties of these two drugs match each other almost closely, hence are selected for combination. They have similar half-lives. Optimum synergistic effect is seen at a concentration ratio of 20:1 (sulphamethoxazole to trimethoprim) in blood and tissues. The advantages of this combination are the following:

• 1.

  Individually, both are bacteriostatic but the combination has cidal effect.

• 2.

  Chances of development of bacterial resistance is greatly reduced.

Cotrimoxazole is well absorbed after oral administration and is also available for parenteral use, widely distributed to various tissues including CSF and sputum, metabolized in liver and excreted mainly in urine; hence, dose reduction is needed in patients with renal insufficiency.

Cotrimoxazole is well tolerated in most patients. Most of the adverse effects are same as those of sulphonamides. The common adverse effects are skin rashes and gastrointestinal (GI) disturbances. Exfoliative dermatitis, erythema multiforme and Stevens–Johnson syndrome are rare. GI symptoms include nausea, vomiting, glossitis and stomatitis. Megaloblastic anaemia due to folate deficiency may occur rarely, especially in alcoholics and malnourished persons. Bone marrow suppression with leucopenia, neutropenia and thrombocytopenia occurs rarely. Cotrimoxazole is contraindicated in pregnancy.

The preparations of cotrimoxazole are shown in Table 11.3 .

• 1.

  Urinary tract infection (UTI): Cotrimoxazole is effective for the treatment of acute uncomplicated lower UTIs due to gram-negative organisms such as E. coli , Proteus and Enterobacter spp. The usual dose is 800 mg sulphamethoxazole plus 160 mg of trimethoprim (cotrimoxazole double-strength tablet) b.d. for 3 days. It is useful for chronic and recurrent lower UTIs especially in women. Small doses of cotrimoxazole daily or thrice weekly are used for long-term prophylaxis in recurrent UTI. Cotrimoxazole can be used in the treatment of bacterial prostatitis as it is concentrated in prostatic tissue.

• 2.

  Respiratory tract infections: Cotrimoxazole is useful for acute and chronic bronchitis due to H. influenzae and Moraxella catarrhalis . It is also useful for acute maxillary sinusitis and otitis media.

• 3.

  Bacterial diarrhoeas: Cotrimoxazole may be used for GI infections due to Shigella , E. coli and Salmonella spp. But FQs are the preferred agents.

• 4.

  Pneumocystis jiroveci infection: High doses of cotrimoxazole are used for treatment of infection due to P . jiroveci in immunocompromised patients. It is useful for treatment as well as prophylaxis of P . jiroveci pneumonia. Pentamidine, clindamycin, primaquine and atovaquone are the alternative drugs for P . jiroveci infection.

• 5.

  Nocardiosis: Cotrimoxazole has been used in the treatment of infection due to Nocardia spp.

• 6.

  Chancroid: It is caused by H. ducreyi . The drug of choice is azithromycin. Cotrimoxazole is equally effective. The alternative drugs are ceftriaxone and ciprofloxacin.

• 7.

  Typhoid fever (see p. 382): Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin, etc.) or third-generation cephalosporins (ceftriaxone and cefoperazone) are the treatment of choice for typhoid fever. Cotrimoxazole may also be effective.

FQs inhibit bacterial DNA synthesis (bactericidal). They inhibit DNA gyrase, thus blocking DNA replication in gram-negative bacteria. Inhibition of topoisomerase IV in gram-positive bacteria prevents separation of replicated DNA.

Ciprofloxacin is the prototype drug. It is highly effective against aerobic gram-negative organisms – E. coli , Enterobacter , Proteus , Klebsiella , Salmonella , Shigella , H. ducreyi , H. influenzae , N. gonorrhoeae , N. meningitidis , V. cholerae and Campylobacter jejuni .

It has activity against S. aureus , Pseudomonas aeruginosa and M. tuberculosis .

Most of the anaerobes, Bacteroides fragilis , C. difficile , etc. are resistant to ciprofloxacin.

Newer FQs like levofloxacin, gemifloxacin and moxifloxacin have greater activity against streptococci and some activity against anaerobes.

Ciprofloxacin is administered by oral, i.v. or topical routes. It is well absorbed from the gut, but food delays its absorption. It is widely distributed in the body, and reaches high concentration in kidney, lung, prostatic tissue, bile, macrophages, etc. It is excreted mainly in urine.

• ■

  The common adverse effects are related to the GI tract, e.g. nausea, vomiting and abdominal discomfort.

• ■

  CNS effects include headache, dizziness, insomnia, confusion, hallucinations and convulsions.

• ■

  Hypersensitivity reactions include skin rashes, urticaria, itching, eosinophilia and photosensitivity.

• ■

  Tenosynovitis and tendon rupture can occur especially in athletes.

• ■

  Moxifloxacin can cause prolongation of QT interval.

• ■

  FQs are contraindicated in pregnancy.

• ■

  FQs have caused cartilage damage in immature animals – hence, they should be avoided in young children.

Drug Interactions. Ciprofloxacin increases the plasma concentration of theophylline, warfarin, etc., by inhibiting their metabolism. Nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate CNS side effects of FQs – confusion, irritability and rarely convulsions may occur. Like tetracyclines, absorption of FQs is reduced by antacids, ferrous salts and sucralfate.

Other FQs have been discussed in Table 11.4 .

Balofloxacin (oral) and pazufloxacin (i.v. infusion) are effective against both gram-positive and gram-negative organisms including methicillin-resistant S. aureus (MRSA). They are used in nosocomial infections.

• 1.

  UTI: FQs are one of the most commonly used AMAs for UTI. They are effective against gram-negative bacilli, such as E. coli , Proteus and Enterobacter . They also have moderate activity against Pseudomonas infection. FQs are superior to cotrimoxazole for the treatment of UTI. They are also effective for the treatment of bacterial prostatitis as they are concentrated in the prostatic tissue (ciprofloxacin 750 mg b.d. for 3 weeks for upper UTI).

• 2.

  Prostatitis: FQs are used in prostatitis as an alternative to cotrimoxazole.

• 3.

  Bacterial diarrhoeas: FQs are effective for a variety of GI infections caused by E. coli , Shigella , Salmonella , etc. For traveller’s diarrhoea (due to E. coli ), FQs are as effective as cotrimoxazole. Norfloxacin, ciprofloxacin or levofloxacin therapy for 3–5 days is adequate.

• 4.

  Typhoid fever: Ciprofloxacin (750 mg orally b.d. for 10 days) is the preferred drug for treatment of typhoid. It is bactericidal and causes rapid resolution of symptoms. Levofloxacin or ofloxacin can also be used. They are also effective in eliminating chronic carrier state of Salmonella typhi when therapy is continued for 4 weeks as they attain effective concentration in bile and intestinal mucosa. Multidrug-resistant (MDR) cases are treated with ceftriaxone (2 g i.v. for 7 days) or azithromycin (500 mg orally daily for 7 days).

• 5.

  Sexually transmitted diseases

  • ■

    Gonococcal infections : FQs were effective for the treatment of cervicitis and urethritis caused by N. gonorrhoeae but their use has declined because of high rates of resistance.

  • ■

    Chancroid: Ciprofloxacin in a dose of 500 mg b.d. for 3 days is effective.

  • ■

    Chlamydial cervicitis and urethritis can be treated with levofloxacin or ofloxacin.

• 6.

  Skin, soft-tissue and bone infections due to S. aureus and gram-negative bacilli require prolonged antimicrobial therapy. FQs can be used in combination with an agent effective against anaerobes especially in diabetic foot infections.

• 7.

  Ciprofloxacin can be used to eradicate meningococci from nasopharynx, thus eliminating the carrier state, but the preferred drug is rifampin.

• 8.

  Mycobacterial infections: In MDR-TB, atypical mycobacterial infections, MAC infection in AIDS patients and leprosy, FQs are used in combination with other AMAs.

• 9.

  Prophylaxis and treatment of infections in neutropenic patients: FQs can be used.

• 10.

  Ciprofloxacin, levofloxacin, moxifloxacin and ofloxacin are used topically for conjunctivitis due to susceptible organisms.

• 11.

  Respiratory infections: Newer FQs (levofloxacin and moxifloxacin) are highly effective for community-acquired pneumonia and chronic bronchitis.

• 12.

  Anthrax: Ciprofloxacin is the preferred drug for treatment and prophylaxis of anthrax.

β-Lactam antibiotics produce bactericidal effect by inhibiting cell wall synthesis in susceptible bacteria.

Cross-linking of peptidoglycan residues and site of action of β-lactam antibiotics.

(Source: Adapted from Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th ed) .

Bacterial cell wall is composed of peptidoglycan which contains amino sugars, N -acetylmuramic acid (NAM) and N -acetylglucosamine (NAG). The enzyme, transpeptidase (a PBP), removes terminal alanine of one strand resulting in its linkage with glycine of adjacent strand. Cross-linking makes the cell wall rigid and stable.

β-Lactams, the structural analogues of d-alanine, inhibit transpeptidase, thus inhibiting cross-linking of peptidoglycans and cell wall synthesis. Cell wall–deficient forms are produced which undergo lysis (bactericidal action). β-Lactams exert their cidal effect when the bacteria are actively multiplying and synthesizing cell wall.

PBPs, consisting of transpeptidase, other enzymes and related proteins, are located in the cell membrane of bacteria. The cell wall in gram-positive bacteria is composed mainly of highly cross-linked peptidoglycan, which is 50–100 layers thick and is near the cell surface. In gram-negative bacteria, the peptidoglycan layer is only one to two molecules thick. In addition, there is an outer lipopolysaccharide layer. Hence, gram-negative organisms are less susceptible to penicillin than gram-positive organisms.

Bacteria develop resistance (i) by producing β-lactamases, which destroy the β-lactam ring, e.g. S. aureus , E. coli , gonococci and H. influenzae , (ii) due to altered PBPs which have less affinity for β-lactams, e.g. S. pneumoniae , and (iii) due to decreased ability of the drug to penetrate to its site of action.

Most of the orally administered penicillin G is destroyed by gastric acid (acid labile); hence, penicillin G is usually given by i.v. route. It can also be administered by i.m. route but is painful. Penicillin G is widely distributed in body tissues, but poorly crosses BBB, although during meningitis, adequate amount reaches the CSF. Penicillin G is rapidly excreted in urine mainly by active tubular secretion. Since renal function is not completely developed in infants and neonates, excretion of penicillins is slow. The action of penicillins can be augmented and prolonged by giving probenecid simultaneously.

The duration of action of penicillin G is increased by combining it with poorly water-soluble compounds, such as procaine (procaine penicillin G) or benzathine (benzathine penicillin G) to yield aqueous suspensions. They are called repository or depot penicillins ( Table 11.5 and Fig. 11.7 ).

Preparations of penicillin G with their duration of action and plasma concentration.

Penicillins are relatively safe. They may cause hypersensitivity reactions, such as skin rashes, urticaria, fever, dermatitis, bronchospasm, angioedema, joint pain, serum sickness or anaphylactic reaction.

The major manifestations of anaphylactic shock are severe hypotension, bronchospasm and laryngeal oedema. It is an immunoglobulin E (IgE)–mediated, immediate type of hypersensitivity reaction (type I hypersensitivity). It is not a dose-related adverse drug reaction and can occur with any dosage form of penicillin. Cross-reactivity can occur among penicillins and also among β-lactam antibiotics.

Owing to the risk of anaphylaxis as well as availability of better AMAs, the use of penicillin G has declined. For uses of PnG, see pp. 387 to 389.

• 1.

  Acid labile – orally not very effective

• 2.

  Short duration of action (to overcome this, repository penicillins have been developed)

• 3.

  Narrow spectrum of antibacterial activity (mainly against gram-positive organisms)

• 4.

  Destroyed by penicillinase enzyme

• 5.

  Possibility of anaphylaxis

To overcome most of the above drawbacks, semisynthetic penicillins have been developed.

(see pp. 387 to 389)

The adverse effects of ampicillin are similar to those of penicillin G but skin rashes and diarrhoea are more common.

They are clavulanic acid, sulbactam and tazobactam. They structurally resemble β-lactam molecules. β-Lactamase inhibitors bind to β-lactamases and inactivate them. Coadministration of these drugs with β-lactams increases the activity of β-lactams by preventing them from enzymatic destruction.

Cephalosporins are administered either orally or parenterally ( Table 11.9 ). These drugs are excreted mainly unchanged through kidney by either glomerular filtration or tubular secretion. Some cephalosporins are metabolized in the body before their excretion. Cefotaxime is deacetylated in the body before its excretion. Cefoperazone is mainly excreted through bile. Like penicillins, the active tubular secretion of cephalosporins is blocked by probenecid, resulting in higher blood levels and longer duration of action.

• 1.

  Hypersensitivity: The most common adverse effects are allergic reactions. They are skin rashes, urticaria and rarely anaphylaxis. Cross-reactivity to penicillin is seen in few patients.

• 2.

  GI disturbances mainly diarrhoea, vomiting and anorexia can also occur.

• 3.

  Pain at the site of i.m. injection mainly with cephalothin. Intravenous cephalosporins can cause thrombophlebitis.

• 4.

  Nephrotoxicity is also seen, particularly with cephaloridine, because of which it has been withdrawn. Coadministration of cephalothin and gentamicin increases the risk of nephrotoxicity.

• 5.

  Intolerance to alcohol (a disulfiram-like reaction) has been reported with cefotetan and cefoperazone.

• 6.

  Severe bleeding can occur due to either hypoprothrombinaemia (which responds to vitamin K therapy) or thrombocytopenia and/or platelet dysfunction, especially in patients with renal failure.

• 1.

  They contain two or more amino sugars attached by glycosidic linkage to hexose ring.

• 2.

  They are highly polar compounds, hence poorly absorbed from the GI tract. They are administered by parenteral route (i.m./i.v.) for systemic effect.

• 3.

  They are mainly distributed into extracellular fluid and poorly penetrate into the CSF.

• 4.

  They are not metabolized in the body.

• 5.

  They are excreted unchanged in urine.

• 6.

  They have bactericidal action against gram-negative aerobes and are more active at alkaline pH.

• 7.

  They cause ototoxicity and nephrotoxicity .

• 8.

  They exhibit partial cross-resistance among them.

• 9.

  Transport of aminoglycosides into the bacterial cell requires oxygen; hence, anaerobes are resistant to aminoglycosides.

Aminoglycosides are bactericidal agents – inhibit protein synthesis.

Bacterial resistance to aminoglycosides is due to (i) inactivation of the drug by bacterial enzymes, (ii) decreased entry of drug into bacterial cell and (iii) decreased affinity of the drug for the ribosomes.

• 1.

  A concentration-dependent killing effect – higher the plasma concentration, more of the bacteria killed rapidly.

• 2.

  A postantibiotic effect – bactericidal effect is present even when serum concentration falls below MIC. Therefore, once-daily dosing regimen is effective.

• 1.

  Once-daily dosing regimen – total daily dose is given as a single injection. It is preferred because it:

  • ■

    Is as effective as multiple-dose regimen. Higher peak plasma concentration is achieved following single dose.

  • ■

    Is safer than multiple-dose regimen. The plasma trough concentration of aminoglycosides remains below threshold levels for toxicity for a long period of time.

  • ■

    Is convenient.

• 2.

  Multiple-daily dosing regimen – the total daily dose is administered in two or three equally divided doses.

Once-daily dosing regimen is not preferred in bacterial endocarditis, children and patients with renal impairment. Dose adjustment of aminoglycosides is done according to body weight and creatinine clearance.

• 1.

  Ototoxicity: Vestibular and cochlear dysfunctions can occur due to VIII cranial nerve damage. Aminoglycosides get concentrated in the perilymph and endolymph of the inner ear which can lead to progressive damage to vestibular and cochlear hair cells. Streptomycin and gentamicin mainly affect vestibular function. Vestibular dysfunction causes intense headache (earliest symptom), dizziness, nausea, vomiting, vertigo, nystagmus and ataxia. Amikacin and kanamycin affect auditory function, causing more cochlear damage. The manifestations of cochlear damage are tinnitus (reversible on discontinuation of the drug) and deafness (permanent).

  • The important risk factors for ototoxicity are the following:

    • (a)

      Elderly patients

    • (b)

      Repeated courses of aminoglycosides

    • (c)

      Persistently increased concentration of the drug in plasma

    • (d)

      Patients with preexisting auditory impairment

    • (e)

      Concurrent use of other ototoxic drugs, such as vancomycin, minocycline and loop diuretics

• 2.

  Nephrotoxicity: Aminoglycosides get concentrated in renal cortex and produce nephrotoxicity, which is usually reversible on discontinuation of the drug. The incidence of nephrotoxicity is highest with neomycin and least with streptomycin. There is a decrease in urinary concentrating capacity, albuminuria, etc. The risk factors for nephrotoxicity are elderly patients, preexisting renal disease and concurrent use of other nephrotoxic drugs, such as AMB, vancomycin, cisplatin and cyclosporine.

• 3.

  Neuromuscular blocking effect: Apnoea and muscular paralysis have been reported. It may be reversed by administration of calcium salt. Aminoglycosides inhibit release of acetylcholine from motor nerve. Myasthenic patients are more susceptible to neuromuscular blocking effect of these drugs; hence, they should be avoided.

• 4.

  Hypersensitivity reactions are rare; occasionally skin rashes, drug fever and eosinophilia can occur. Cross-sensitivity between aminoglycosides may occur.

• 5.

  Use of aminoglycosides during pregnancy may cause ototoxicity in fetus.

• ■

  Topically

  • (a)

    Infections of the skin and mucous membranes: Ulcers, wounds and burns.

  • (b)

    Infections of the eye and external ear: Neomycin is often used in combination with bacitracin or polymyxin B.

• ■

  Orally (for local action)

  • (a)

    Neomycin sulphate is useful in combination with erythromycin base for preparation of bowel before abdominal surgery.

  • (b)

    Hepatic encephalopathy: Neomycin, on oral administration, reduces blood ammonia level by destroying the colonic bacteria. Neomycin is highly toxic; hence, it has been replaced by oral lactulose, which is preferred for hepatic encephalopathy.

Bacterial resistance to tetracyclines is due to: (i) decreased influx or increased efflux of tetracyclines and (ii) inactivation of the drug by enzymes.

The older tetracyclines are incompletely absorbed after oral administration ( Table 11.10 ), but that is adequate to produce antibacterial activity. Food interferes with the absorption of all tetracyclines; doxycycline and minocycline are less affected. Tetracyclines have chelating property, hence form stable insoluble and unabsorbable complexes with calcium, magnesium, iron and other metal ions. Therefore, the absorption of tetracyclines is reduced by simultaneous administration with dairy products, antacids, iron, sucralfate and zinc salts. Tetracyclines are widely distributed throughout the body, and get concentrated in liver, spleen, bone, dentine, enamel of unerupted teeth but concentration in CSF is relatively low. They cross placental barrier, and are metabolized in liver and excreted in urine. Doxycycline is excreted mainly in the faeces via bile. Therefore, doxycycline is safe for use in patients with renal insufficiency. Doxycycline undergoes enterohepatic cycling.

• 1.

  GI: On oral administration, they can cause GI irritation manifested as nausea, vomiting, epigastric distress, abdominal discomfort and diarrhoea. Diarrhoea is more common with tetracycline and oxytetracycline as they are incompletely absorbed → cause alteration of normal flora. Risk of diarrhoea is low with doxycycline.

• 2.

  Phototoxicity: It is particularly seen with demeclocycline and doxycycline. They may also produce sunburn-like reaction in the skin on exposure to sunlight. They may also produce pigmentation of nails.

• 3.

  Hepatotoxicity: Acute hepatic necrosis with fatty changes is common in patients receiving high doses (>2 g/day) intravenously. It is more likely to occur in pregnant women.

• 4.

  Renal toxicity: Demeclocycline may produce nephrogenic diabetes insipidus by blocking the action of antidiuretic hormone (ADH) on collecting duct. This effect of demeclocycline has been used therapeutically in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

  • Fanconi syndrome: Use of outdated tetracyclines may damage proximal renal tubules – the patient may present with nausea, vomiting, polyuria, proteinuria, acidosis, etc.

• 5.

  Superinfection: It is common with older tetracyclines because of their incomplete absorption in the gut; they cause alteration of the gut flora. Superinfection occurs with organisms like Candida , Proteus , Pseudomonas and C. difficile . Pseudomembranous colitis caused by C. difficile is a serious complication. It is characterized by severe diarrhoea, fever, abdominal pain and stool mixed with blood and mucus, which is treated with oral metronidazole.

• 6.

  Effects on bones and teeth: Tetracyclines have calcium chelating property and form tetracycline–calcium orthophosphate complex which is deposited in growing bone and teeth. Use of tetracyclines in children and during pregnancy can cause permanent brownish discolouration of deciduous teeth due to deposition of chelate in the teeth. There is increased incidence of caries in such teeth. Tetracyclines also affect the linear growth of bones. The incidence of hepatotoxicity is more in pregnant women. Therefore, tetracyclines are contraindicated during pregnancy in the interest of both fetus and mother. It is also contraindicated in children up to the age of 8 years.

• 7.

  They may cause increased intracranial pressure (pseudotumour cerebri) in infants.

• 8.

  Hypersensitivity reactions: Skin rashes, fever, urticaria, exfoliative dermatitis, etc., may occur rarely. Cross-sensitivity among tetracyclines is common.

• 1.

  Rickettsial infections: Tetracyclines are the first-choice drugs for the treatment of rickettsial infections – epidemic typhus, Rocky Mountain spotted fever, scrub typhus, rickettsial pox and Q fever. Doxycycline 100 mg b.d. is given orally or intravenously for 5–7 days.

• 2.

  Mycoplasma pneumoniae infections : Doxycycline has good activity against Mycoplasma – used to shorten the duration of illness. It is a first choice drug in atypical pneumonia due to M. pneumoniae .

• 3.

  Chlamydial infections

  • Lymphogranuloma venereum: It is a sexually transmitted infection caused by C. trachomatis . Doxycycline is the drug of choice. In complicated cases (i.e. pelvic inflammatory disease), doxycycline 100 mg b.d. should be continued for 21 days. Macrolides are also effective.

  • Chlamydial urethritis and granuloma inguinale: Doxycycline is highly effective and is the drug of choice.

  • Psittacosis: Doxycycline is the preferred agent; treatment should be continued for 2 weeks to prevent relapse.

• 4.

  Cholera: Fluid and electrolyte replacement is the mainstay of therapy. Single dose of tetracycline 2 g or doxycycline 300 mg is effective in adults. It reduces the stool volume.

• 5.

  Brucellosis: Treatment of choice is a combination of doxycycline with rifampin/gentamicin/streptomycin.

• 6.

  Plague: Doxycycline is highly effective for treatment of plague.

• 7.

  As an alternative drug: For treatment of leptospirosis (doxycycline is an alternative to penicillins), pneumonia due to Chlamydia pneumoniae (doxycycline alternative to azithromycin), tularaemia (alternative to streptomycin, gentamicin), etc.

• 8.

  Acne: Low doses of tetracyclines are used.

  

  • Tetracyclines act by inhibiting propionibacteria, thereby prevent the formation of free fatty acids.

• 9.

  Malaria: Doxycycline is used in combination with other antimalarial agents for treatment of chloroquine-resistant P. falciparum malaria. It is used alone for malarial chemoprophylaxis.

• 10.

  Amoebiasis: See p. 452.

• 11.

  SIADH: Demeclocycline has anti-ADH action; hence, it is used in SIADH to promote diuresis.

• 12.

  Leprosy: It is one of the components in ROM (rifampin, ofloxacin and minocycline) regimen for single-lesion paucibacillary leprosy (PBL).

• 13.

  Filariasis : Doxycycline is given orally in filarial infection.

Chloramphenicol is a bacteriostatic agent, but in high concentration, it can be bactericidal against H. influenzae , N. meningitidis and S. pneumoniae . It can also inhibit mitochondrial protein synthesis in mammalian cells by acting on 70S ribosomes.

Resistance to chloramphenicol is caused by:

• 1.

  Production of inactivating enzyme – acetyltransferase, e.g. H. influenzae , S. typhi , S. aureus

• 2.

  Decreased permeability of the microbial cell wall

• 3.

  Ribosomal mutation

Chloramphenicol is commonly given by oral route and is rapidly absorbed from the gut. It is also available for parenteral and topical administration. It has a bitter taste; to improve the taste, chloramphenicol palmitate suspension has been developed for paediatric use. It gets activated in the intestine by pancreatic lipase. Chloramphenicol is widely distributed to all tissues including CSF and brain. It also crosses placental barrier and is secreted in milk. It gets metabolized in liver by glucuronide conjugation and the metabolite is excreted mainly in urine.

Most of the adverse effects of chloramphenicol are due to inhibition of mammalian mitochondrial protein synthesis.

• 1.

  Hypersensitivity reactions: Skin rashes, drug fever and angioedema may occur rarely.

• 2.

  Bone marrow suppression: The most serious adverse effect of chloramphenicol is on bone marrow. It can occur in two ways:

  • (a)

    Dose-dependent reversible suppression of bone marrow, which manifests as anaemia, leucopenia and thrombocytopenia

  • (b)

    Idiosyncratic non-dose-related irreversible aplastic anaemia, which is often fatal

• 3.

  GI effects: These include nausea, vomiting and diarrhoea. Prolonged use may cause superinfection due to suppression of gut flora.

• 4.

  Gray baby syndrome: In neonates, especially in premature babies, chloramphenicol can cause a dose-related gray baby syndrome due to reduced degradation and detoxification of the drug in liver because of the deficiency of glucuronyl transferase enzyme. The manifestations are nausea, vomiting, abdominal distension, diarrhoea, refusal to suck, cyanosis, irritability and circulatory collapse. The skin appears ashen gray colour, hence the name ‘gray baby’ syndrome. Mortality is high. Therefore, chloramphenicol should be avoided in neonates.

Drug interactions : Like erythromycin, chloramphenicol increases plasma concentration of certain drugs, such as warfarin, phenytoin, rifabutin and antiretroviral protease inhibitors (PIs), by inhibiting hepatic cytochrome P450 isoenzymes.

• 1.

  Typhoid fever: Chloramphenicol was the first-choice drug for typhoid. Antibiotics useful in typhoid are third-generation cephalosporins, FQs, azithromycin, ampicillin, cotrimoxazole, etc. Now, FQs (ciprofloxacin, ofloxacin, levofloxacin, etc.) or third-generation cephalosporins (ceftriaxone, cefoperazone) are the drugs of choice for typhoid fever. The dose of ciprofloxacin is 750 mg 12 hourly for 10 days. It also eliminates carrier state. MDR cases are treated with ceftriaxone (2–4 g i.v. daily for 10 days) or azithromycin.

• 2.

  Bacterial meningitis: Third-generation cephalosporins are the preferred drugs for the treatment of bacterial meningitis caused by H. influenzae , N. meningitidis and S. pneumoniae . However, chloramphenicol can be used alone or in combination with ampicillin.

• 3.

  Anaerobic infections: Chloramphenicol is effective against most anaerobic bacteria including B. fragilis . It is often used in combination with metronidazole for the treatment of brain, lung, intra-abdominal or pelvic abscesses.

• 4.

  Rickettsial infections: Tetracyclines are the drugs of choice for the treatment of rickettsial diseases. Chloramphenicol can be used to treat rickettsial infections in children and pregnant women.

• 5.

  Eye and ear infections: Chloramphenicol is used topically for eye and ear infections due to susceptible organisms.

• 6.

  Brucellosis : Chloramphenicol can be used when tetracyclines are contraindicated.

E rythromycin and other macrolides bind to bacterial 50S ribosomal subunit and inhibit protein synthesis. They are bacteriostatic, but at high concentrations, they can act as bactericidal agents. They are more active at alkaline pH.

Erythromycin is adequately absorbed from the upper GI tract. It is destroyed by gastric acid (acid labile), hence must be administered as E nteric-coated tablets to protect it from gastric acid. Food may delay the absorption of erythromycin. It is widely distributed in the body and reaches therapeutic concentration in prostatic secretions but does not cross BBB. It is partly metabolized in liver and excreted in bile.

They are erythromycin base, E rythromycin E stolate and erythromycin stearate.

• 1.

  The common side effects are related to the GI tract ( E nteral toxicity): Nausea, vomiting, epigastric pain and diarrhoea. Erythromycin increases GI motility by stimulating motilin receptors in the gut.

• 2.

  Hypersensitivity reactions: Skin rashes, drug fever, eosinophilia and hepatitis with cholestatic jaundice, particularly with erythromycin estolate. Incidence of hepatotoxicity is more in pregnant women.

  

Erythromycin and clarithromycin are E nzyme inhibitors, hence increase the blood levels of a number of drugs, such as theophylline, carbamazepine, valproate, warfarin, digoxin and cyclosporine, and potentiate their effects. Erythromycin and clarithromycin can precipitate fatal ventricular arrhythmias when given with cisapride, astemizole, terfenadine, etc. – such interactions are not seen with azithromycin.

• 1.

  It has a narrow spectrum of antibacterial activity.

• 2.

  Its oral bioavailability is low.

• 3.

  It has a short duration of action.

• 4.

  Poor patient compliance due to GI side effects.

To overcome the above drawbacks, semisynthetic macrolides – roxithromycin, clarithromycin and azithromycin – have been developed ( Table 11.11 ).

• 1.

  As a drug of choice in the following conditions:

  • (a)

    M. pneumoniae infections: Azithromycin and clarithromycin are often used for the treatment of community-acquired pneumonia. Erythromycin can also be used.

  • (b)

    Legionnaires’ pneumonia: Macrolides, especially azithromycin, is the drug of choice because of high tissue concentration, excellent activity, better tolerability and single daily dosing.

  • (c)

    Chlamydial infections: Azithromycin is the first choice drug in urethritis, lymphogranuloma venereum and chlamydial pneumonia. Macrolides are preferred for chlamydial infections in children and pregnant women.

  • (d)

    Diphtheria: Erythromycin is very effective for eliminating the carrier state and for the treatment of acute infection.

  • (e)

    Pertussis (whooping cough): Erythromycin is most effective for the treatment as well as for prophylaxis of close contacts. Clarithromycin and azithromycin are also effective.

  • (f)

    Chancroid: Azithromycin is effective as single dose in chancroid.

• 2.

  As an alternative drug in patients who are allergic to penicillins/cephalosporins

  • (a)

    Tetanus: Administration of human tetanus antitoxin, tetanus toxoid, anticonvulsant (e.g. diazepam) and debridement of wound are important therapeutic measures. A course of oral erythromycin for 10 days may be given to eradicate C. tetani .

  • (b)

    Streptococcal infections: Tonsillitis, pharyngitis, otitis media, cellulitis, pneumonia, etc., respond to azithromycin and erythromycin.

  • (c)

    MDR typhoid fever: It is an alternative to cephalosporins.

  • (d)

    Prophylactic uses

    • ■

      Before surgical procedures to prevent bacterial endocarditis in patients with valvular lesion – azithromycin or clarithromycin can be used.

    • ■

      For prophylaxis of recurrences of rheumatic fever.

• 3.

  Other Uses. For treatment of MAC infections in AIDS patients, azithromycin/clarithromycin is used in combination with other drugs. Clarithromycin is also useful in the treatment of H. pylori infection and leprosy along with other drugs.

Treatment schedules (empirical therapy)

• ■

  Ciprofloxacin 250–500 mg b.d. oral for 3 days

• ■

  Norfloxacin 400 mg b.d. oral for 3 days

• ■

  Ofloxacin 200 mg b.d. oral for 3 days

• ■

  Cefpodoxime proxetil 200 mg b.d. for 3–5 days

• ■

  Cotrimoxazole DS b.d. oral for 3 days

• ■

  Nitrofurantoin 100 mg b.d. for 5 days